Immunotherapy for Treatment of Multiple Sclerosis & the Role of Myelin-Sensitive MRI
Cornelia Laule1
1University of British Columbia, Canada

Synopsis

Conventional MRI plays a major role in evaluating new multiple sclerosis (MS) immunotherapies. However, proton density, T1-weighted, T2-weighted and volumetric imaging have low pathological specificity and poor sensitivity for non-lesional disease, driving the development of new techniques to measure myelin, which is the primary target of damage in MS. Each technique has different strengths and weaknesses with respect to myelin-specificity and myelin-sensitivity. The choice of method ultimately depends on the research or clinical question being asked.

BACKGROUND

Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) which affects over 2.8 million people worldwide. MS is the most common, non-traumatic cause of disability in young adults, with women being diagnosed 2-3 times more often than men. While there is evidence of a genetic component, the cause of MS is unknown and there is no cure. MS is autoimmune in nature, where the body's immune system attacks its own tissues. Within the CNS, the immune system causes inflammation that primarily damages myelin (the insulating sheath surrounding nerve fibers), along with the cells that make myelin and the nerve fibers themselves. A variety of different therapies have emerged over the last three decades that modulate the immune system to prevent new inflammation, with the hope of facilitating repair and preventing ongoing damage. Conventional magnetic resonance imaging (MRI) plays a major role in MS diagnosis, as well as evaluating new treatments. However, proton density, T1-weighted, T2-weighted and volumetric imaging have low pathological specificity and poor sensitivity for non-lesional disease, driving the development of new quantitative imaging techniques to measure myelin in MS.

OBJECTIVE

To provide an overview of MS immunotherapies and imaging approaches for assessing myelin in MS.

COMMON MYELIN-SENSITIVE IMAGING METHODS

Magnetization transfer imaging (MTI) examines the interaction between macromolecules and water. It is influenced by myelin, but also inflammation, axonal loss and gliosis. Newer approaches such as inhomogeneous magnetization transfer may be more specific to myelin lipids.
Diffusion tensor imaging (DTI) measures water motion. Measures are affected by myelin, but also axonal density, fibre orientation and membrane permeability. MS lesions make tractography and interpretation difficult. Newer modeling approaches such as diffusion basis spectrum imaging may provide more specific information about tissue microstructure and inflammation/edema.
Magnetic resonance spectroscopy (MRS) measures N-acetylaspartate (axon-myelin coupling), choline (membrane turnover) and free lipid (active demyelination). MRS has limited resolution and volumetric coverage.
Myelin water imaging (MWI) measures water trapped within myelin bilayers. It is specific for myelin, but water exchange may be a confounder. mcDESPOT is a proposed high-volumetric alternative for quantifying myelin water. Analysis is complicated and there is some discrepancy between MWI and mcDESPOT.
T1-weighted/T2-weighted imaging can probe cortical myelin, but evidence is lacking for white matter.
Susceptibility weighted imaging reflects tissue microstructure, including myelin, but also iron. It is commonly available, fast to acquire and high resolution.
Positron emission tomography (PET) labels proposed myelin targets using injected radioisotopes. It is sensitive, but availability, cost and ionizing radiation are limitations.

CONCLUSIONS

A variety of imaging methods can probe changes to myelin in MS in the context of immunotherapy, each with different strengths and weaknesses with respect to myelin-specificity and myelin-sensitivity. The choice of optimal method ultimately depends on the research or clinical question being asked.

Acknowledgements

Thank you to study volunteers, tissue donors and families for participating in research studies presented within this talk. Funding support was provided by the Natural Sciences and Engineering Research Council of Canada (NSERC), the Craig H. Nielsen Foundation, the Multiple Sclerosis Society of Canada and the International Collaboration On Repair Discoveries (ICORD). UBC and ICORD are located on the traditional, ancestral, and unceded territories of Coast Salish Peoples, including the territories of the xwməθkwəy̓əm (Musqueam), Skwxwú7mesh (Squamish), Stó:lō and Səl̓ílwətaʔ/Selilwitulh (Tsleil- Waututh) Nations.

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Proc. Intl. Soc. Mag. Reson. Med. 30 (2022)